The transition from persistent to lytic infection by the human immunodeficiency virus is marked by a burst of viral replication and gene expression that is linked to the antigen induced immune activation of HIV-infected cells. This process occurs through the transcriptional activation of viral genes by the interaction of both cellular and virally derived factors with numerous regulatory cis-elements present in the HIV-1 long terminal repeat. The overlapping requirement between T-cell lymphokine genes such as interleukin 2 and the HIV-LTR for specific cellular factors forges the inextricable link between T-cell activation and activation of the HIV-LTR. We have found that prior treatment of human T-cells in culture with a calcium response modifier, carboxyamido-triazole, CAI (an oral drug currently in phase I clinical trials as an antimetastatic agent), completely inhibits mitogen stimulated transcription from the HIV-LTR. This effect is specific for the HIV-LTR as other mitogen activated transcription factors such as AP-1 are not affected by the drug. Biochemical analysis of other T-cell transcription factors important in T-cell activation show that CAI greatly inhibits both in vivo and in vitro function of calcium dependent transacting factors such as NF-AT. Preliminary biochemical characterization of DNA binding activity in nuclear extracts from T-cells activated in the presence or absence of CAI shows complete inhibition of NF-AT DNA binding activity. Similar analysis of transcription factor complexes important in HIV-LTR transactivation show near complete inhibition of the cooperative binding by NF-kappa B and Sp-1 to specific promoter elements within the HIV-LTR. No effect was observed on AP-1 DNA binding activity. Transient transfection experiments identify the NF-kappa B sites as the major, though not exclusive sites of CAI action within the HIV-LTR. Current efforts are directed at characterizing further the elements within the HIV-LTR that are critical for CAI mediated inhibition of activated transcription from the HIV-LTR.